The suppression of appetite with 1-(o-chlorophenyl)-2-methyl-2-propylamine and acid-addition salts thereof



United States Patent THE SUPPRESSION OF APPETITE WITH l-(O-CHLO-ROPHENYL)-2-METHYL-2-PROPYLAMINE AND ACID-ADDITION SALTS THEREOF DomVincent Finocchio, Summit, and Charles Ferdinand Huebner, Chatham, N.J.,assignors to Ciha Corporation, New York, N.Y., a corporation of DelawareNo Drawing. Continuation-impart of application Ser. No. 393,360, Aug.31, 1964. This application Dec. 1, 1966, Ser. No. 598,162

7 Claims. (Cl. 424-330) ABSTRACT OF THE DISCLOSURE Novel anoreticcompositions comprising essentially a pharmacologically effective amountof 1 (o chlorophenyl)-2-methyl-2-propylamine or a pharmaceuticallyacceptable acid-addition salt thereof as the active anoretic ingredient,and a pharmaceutically acceptable carrier.

This is continuation-impart application of our application Ser. No.393,360, filed Aug. 31, 1964, which in turn is a continuation-in-partapplication of our application Ser. No. 285,885, filed June 6, 1963,which in turn is a continuation-in-part application of our applicationSer. No. 200,048, filed June 5, 1962, all of which are now abandoned.

Known appetite suppressant compositions usually contain as the anoreticprinciple compounds having as the common structural characteristic a2-phenylethylamine portion, such as, for example, d,l-l-phenyl-Z-propylamine (d, l-amphetamine)d-l-phenyl-Z-propylamine(d-amphetamine), N-methyld-phenyl-2 propylamine (methamphetamine),3-methyl-2-phenyl-morpholine (phenmetrazine) and the like. However,apart from their appetite suppressant effects, all of these compoundsexert other pharmacological activities which limit their effectivenessin the treatment of obesity: At doses necessary to suppress theappetite, they show stimulating and very often hypertensive properties.Since many obese patients requiring suppression of the appetite oftenshow a latent overstimulation and nervousness, such conditions can beseriously aggravated by administering an anoretic compound withstimulating properties. In order to counteract the stimulating effectsof such compounds, many anoretic preparations are combinationpreparations, which in addition to the appetite suppressant compoundcontain a sedative agent, e.g. S-ethyl 5 phenyl-barbituric acid(phenobarbital), 5-ethyl-5-(l-methyl-butyl) barbituric acid(pentobarbital) and the like, or a tranquilizing or muscle rel-axingcompound, e.g. 1 (p-chloro-u-phenyL benzyl)-4-(2-hydroxyethoxyethyl)piperazine (hydroxyzine), 2-chloro-10-[3-(4-methyl-l-piperazino)propyl]- phenothiazine (proclorperazine), 2-methyl-2-n-propyl-13-propanediol dicarbamate (meprobamate) and the like.

Holm et al., Acta pharmacol and toxicol, 17, pp. 121- 136 (1960)discloses the l-(o-chloro-phenyl)-2-methyl-2- propylamine used in thecompositions of the present invention as well as the 1-(m-chlorophenyl)and l-(pchloro-phenyD-isomers of that'compound, but indicatenon-equivalence in concluding that thefirst named compound is useless asan anoretic agent in the manner in which it was compounded while thelatter two compounds are useful for that purpose when tested in thatmanner; on page 134 of this reference, it is stated that For chlorinesubstituted compounds anorexigenic action required the chlorine atom inthe para or meta position.

Furthermore, compositions containing appetite suppressant compounds withblood pressure raising effects are usually not recommended and evencontra-indicated for the treatment of obese patients with hypertensiveconditions.

Either the addition of a sedative or tranquilizing drug to an anoreticcomposition to offset stimulating properties of the anoretic principleor the contra-indication of such compositions in the treatment of obesepatients with hypertensive conditions is a serious drawback, because theproper balancing between stimulation and sedative depends largely on thereactions of the individual patient to the two types of drugs;furthermore, the majority of clinically obese patients require reductionof weight and suppression of the appetite because of hypertensiveconditions.

A primary object of our invention is to provide a new method for thesuppression of the appetite by administering to a host (e.g. human)requiring such treatment a new anoretic composition, which does not haveor only to a negligible degree the undesirable side effects of knownanoretic compositions.

It is another object of our invention to provide a new method for thesuppression of the appetite by administering to a host (e.g. human)requiring such treatment a new anoretic composition which is free fromany effects on the blood pressure.

A further object of our invention is the provision of a new method forthe suppression of the appetite by administering to a host (e.g. human)requiring such treatment a new anoretic composition which at a dosecontrolling and suppressing the appetite does not have or only to anegligible degree effects on the central nervous system, such as thestimulating properties usually associated with known anoreticcompositions.

We have now found that the appetite can be suppressed without noticeableside effects by administering a new composition comprising essentially apharmacologically effective amount of l-(o-chloro-phenyl) 2 methyl-2-propylamine, having the formula or a pharmaceutically acceptable acidaddition salt thereof, as the active anoretic ingredient, and apharmaceutically acceptable carrier.

Pharmaceutically acceptable acid addition salts ofl-(ochloro-phenyl)-2-rnethyl-2-propylamine are those with inorganicacids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids andthe like, or with organic acids, such as organic carboxylic acids, e.gacetic, propionic, glycolic, malonic, succinic, maleic, hydroxymaleic,fumaric, malic, tartaric, citric, glucuronic, benzoic, salicylic,4-aminosali' cylic, Z-acetoxybenzoic, pamoic, nicotinic acid and thelike, or organic sulfonic acids, eg methane sulfonic, ethane sulfonic,Z-hydroxyethane sulfonic, ethane 1,2-disulfonic, benzene sulfonic,p-toluene sulfonic, naphthalene 2-sulfonic acid and the like.

We have found that l-(o-chloro-phenyl)-2-methyl-2- propylamine or itsacid addition salts exhibit anoretic properties Without having anyeffects on the blood pres sure; especially they do not elevate thelatter above its normal value. Furthermore, We have found that thesecompounds, unlike others having similar Z-phenylethylamine structures,for example, 2 methyl 1 phenyl-2- propylamine, 1 (pchloro-phenyl)-2-methyl-2-propylamine and the like, have no substantialstimulating effects at doses which effectively suppress the appetite.Behavior studies with monkeys show that with the exception of theappetite none of the normal reactions of the test animal, particularlyits mood, are affected to any noticeable degree. These findings are incontrast with the results obtained with other anoretic drugs having thebasic 2-phenylethylamine structure, which above all show pronouncedstimulating effects in test animals.

A preferred method for the suppression of appetite comprisesadministering a new composition comprising essentially apharmacologically effective amount of a pharmaceutically acceptable acidaddition salt of l-(ochloro-phenyl)-2-methyl-2-propylamine, such as thel-(ochloro phenyl) 2-methyl-2-propylamine hydrochloride and the like, asthe active anoretic ingredient, and a pharmaceutically acceptablecarrier.

Also included within the scope of this invention are the new anoreticcompositions, which comprise essentially a pharmacologically effectiveamount of 1- (o -chlorophenyl)-2-methyl-2-propylamine or apharmaceutically acceptable acid addition salt thereof, as the activeanoretic ingredient, and a pharmaceutically acceptable carrier.

Preferred compositions for the suppression of appetite compriseessentially a pharmacologically effective amount of a pharmaceuticallyacceptable acid addition salt of l-(o-chlorophenyl)-2-methyl-2-propylamine, such as the 1-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride and the like, asthe active anoretic ingredient, and a pharmaceutically acceptablecarrier.

The formulation of the compositions of this invention is carried out inthe manner normally employed in the art, usually by combining thepharmacologically active ingredient with a pharmaceutically acceptableorganic or inorganic carrier in specified proportions. The compositionsof this invention are made up to contain at most equal amounts of thepharmacologically active compound and the carrier, such as from aboutpercent to at most 50 percent, by weight, of the active anoreticingredient.

The tablet, capsule, dragee and the like provide for the oral form ofadministration. These orally applicable compositions are compounded tohave per single dosage unit from about 0.025 g. to about 0.075 g., ofthe active anoretic ingredient; the latter is preferably used in theform of a pharmaceutically acceptable acid addition salt thereof, suchas one of the above-mentioned salts with an inorganic or organic acid.It has been found that an average adult dose of about to 75 mg. per day(preferably 50 mg. per day) is effective in humans.

Apart from the active anoretic ingredient, the orally applicablepreparations contain carrier materials commonly employed in thepharmaceutical art for preparing dosage unit compositions, such astablets, capsules, dragees. These include excipients, binders, fillers,lubricants, stabilizers and the like. Examples of such carrier materialsare starches, e.g. corn starch, wheat starch and the like, sugars, e.g.lactose, sucrose and the like, stearic acid or salts thereof, e.g.magnesium stearate, calcium stearate and the like, aluminum magnesiumsilicate preparations (colloidal silica preparations), talcum,tragacanth, acacia, polyethylene glycol and the like. The quantities ofthese ingredients may vary widely and depend upon the physicalcharacteristics (e.g. softness and the like) and size of the orallyapplicable composition, the method of its manufacture and the like.Encapsulation may also be eifected using, if necessary, the sameexcipicuts as those employed for the manufacturing of the tablets. Anycompatible color, approved and certified under the provisions of theFederal Food, Drug and Cosmetic law maybe used as a means ofidentification and the like.

Special orally applicable compositions may also provide for a prolongedand sustained anoretic effect. For example, tablets, such as thosedescribed in US. Patent 2,887,- 738, may contain the pharmacologicallyactive ingredient embedded in a pharmaceutically acceptable waxy core(for prolonged absorption in the lower intestine), around which iscompressed a granulated mixture of the active ingredient together with apharmaceutically acceptable carrier (for immediate absorption in thestomach). Or, capsules having prolonged effects may contain micro-pillscontaining small amounts of the pharmacologically active ingredient withcoats of diiferent rates of degradation. These long-acting preparationsare prepared according to Well known methods.

Other suitable pharmaceutical preparations for the suppression of theappetite containing from about 10 percent to about 50 percent, ofl-(o-chloro-phenyl)-2-methyl-2- propylamine or a pharmaceuticallyacceptable acid addition salt thereof, as the active anoreticingredient, are, for example, orally administered confectionerycompositions, such as elixirs and syrups, parenteral solutions and thelike. These preparations are manufactured according to methodsestablished in the pharmaceutical arts using appropriate carriermaterials. Elixirs are, for example, solutions of the pharmacologicallyactive ingredient in water containing a small amount, for example, aboutfive percent, of ethanol, and sugar substitute, as well as flavor and/or coloring preparations. In view of the fact that the active anoreticingredient, particularly in the form of its acid addition salt, is awater-soluble substance, parenteral solutions contain water (purifiedfor the use in parenteral solutions) as the primary solvent; othersolvents are, for example, lower alkanols, e.g. ethanol and the like, oraqueous mixtures thereof. Other ingredients are added to ensure stablesolutions, for example, stabilizers, such as anti-oxidants, e.g.thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteinehydrochloride, Sodium formaldehyde sulfoxylate, monothioglycerol,thiosorbitol and the like, solubilizers, e.g. N,N-diethylacetamide,polyethyleneglycols, ureas, urethanes and the like, buifers or bufiercombinations, to maintain a preferable pH of about 7, for example,acetic acid, potassium phthalate and sodium hydroxide, potassiumdihydrogen phosphate and disodium hydrogen phosphate, potassiumdihydrogen phosphate and sodium hydroxide, acetic acid and sodiumacetate, and the like, salts for isotonic solutions, e.g. sodiumchloride and the like.

The following working examples are illustrative of the invention, butare in no way intended to limit its scope.

EXAMPLE 1 Tablets, each containing 0.05 g. of 1-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride as the pharmacologically activeingredient, are prepared as follows (for 10,000 tablets):

Alcohol 3A, 50 percent, q.s.

The tragacanth, the l-(o-chloro-phenyl)-2-methyl-2-propylaminehydrochloride and 1,000 g. of lactose are placed in a suitable mixer andblended to homogeneity. The balance of the lactose and the corn starchare added, and the granulate is formed by adding the alcohol. Afterpassing the granulate through a mill, using a No. 4 screen and mediumspeed, it is dried with circulating dehumidified air, and again passedthrough a mill using a No. 2 screen. The broken granulate is returned tothe mixer, the talcum and the magnesium stearate are added and mixing iscontinued. The resulting mass is compressed into tablets weighing 0.2 g.each, using inch punches and dies.

In the above example, the hydrochloride ofl-(o-chlorophenyl)-2-methyl-2-propylamine may be replaced by anothersalt, such as the sulfate, tartrate, citrate, methane sulfonate,naphthalene 2-sulfonate and the like, of 1-(0- chloro-phenyl)-2-methy1-2propylamine.

EXAMPLE 2 Tablets, each containing 0.075 g. ofl-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride as thepharmacologically active ingredient, are prepared as follows (for 5,000tablets):

Ingredients: G.

1 (o-chloro-phenyl) 2 methyl-Z-propylamine hydrochloride 375.00 Lactose,U.S.P. 480.00 Tragacanth 25.00 Talcum, U.S.P. 25.00 Wheat starch 25.00Magnesium stearate 70.00

Alcohol 3A, 50 percent, q.s.

The tablets, each weighing 0.2 g., are prepared according to theprocedure described in Example 1.

EXAMPLE 3 Tablets for the sustained release of the anoretic compound,consisting of a core having 0.067 g. of l-(o-chlorophenyl 2 methyl 2propylamine hydrochloride, and a coating having 0.033 g.-ofl-(o-chloro-phenyl)-2 methyl- 2-propylamine hydrochloride as thepharmacologically active ingredient, are prepared as follows (for 10,000tablets):

(A) Core formulation Ingredients: G.

1 (o-chloro-phenyl) 2 methyl-Z-propylamine hydrochloride 670.00 Carnaubawax 655.00 Stearyl alcohol 655.00 Magnesium stearate 20.00

(B) Coating formulation Ingredients: G.

1 (o-chloro-phenyl) 2 methyl-2-propylamine hydrochloride 330.00Polyethyleneglycol 6000 132.50 Acacia 53.00 Tragacanth 53.00 Lactose1551.45 Confectioners sugar 397.50 Talcum 132.55

Alcohol 3A, 50 percent, q.s.

The l-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride, theacacia, the tragacanth, the lactose, the confectioners sugar and thetalcum are mixed in a suitable mixer. The polyethyleneglycol 6000 isdissolved in the alcohol and added to the above mixture to form thegranulate, which is passed through a No. 16 screen, dried and againpassed through a No. 16 screen. A coating of this material, weighing0.265 g. each, is then compressed around the previously-described core,using 2 inch punches on the Manesty Dry Cota machine. The total weightof the sustained-release tablet is 0.465 g.

Inthe above formulation, the hydrochloride ofl-(ochloro-phenyl)-2-methyl-2-propylamine may be replaced by anothersalt, such as the sulfate, tartrate, citrate, methane sulfonate,naphthalene 2-sulfonic and the like, ofl-(o-chloro-phenyl)-2-methyl-2-propylamine.

'EXAMPLE 4 Capsules, each containing 0.05 g. ofl-(o-chlorophenyl)-2-methyl-2-propylamine hydrochloride as thepharmacologically active ingredient, are prepared as follows (for 1,000capsules):

Ingredients G.

l-(o-chloro-phenyl) 2 methyl 2 propylamine hydrochloride 50.00

Lactose, U.S.P. 130.00

The ingredients are blended in a suitable mixer, sieved through a No. 40screen and again mixed; portions, each weighing 0.18 g. of the resultingmixture are filled into No. 4 capsules.

EXAMPLE 5 Capsules, each containing 0.075 g. ofl-(o-chlorophenyl)-2-methyl-2-propylamine hydrochloride as thepharmaoologically active ingredient. are prepared as follows (for1,000,000 capsules):

Ingredients:

1 (o chloro phenyl) 2 methyl 2- propylamine hydrochloride 75,000.0Magnesium Stearate 20,0000 Lactose, U.S.P. 205,000.0

The ingredients are blended for twenty minutes in a suitable mixer,passed through a 20 mesh screen, and filled in portions of 0.3 g. intoNo. 2 capsules.

In the above formulation, the hydrochloride of 1-(0-chloro-phenyl)-2-methyl-2-propylamine may be replaced by another salt,such as the sulfate, tartarate, citrate, methane sulfionate, naphthalene2-sulfonate and the like, of l-(o-chloro-phenyl)-2-methyl-2-propylamine.

EXAMPLE 6 A syrup, formulated to provide a dosage unit of about 0.050 g.per dosage unit, is prepared as follows:

Ingredients: Kg.

l-(o-chl-oro phenyl)-2-methyl-2-propylamine hydrochloride 1.000 Sodiumsaccharin 0.020 Sodium sucaryl 0.200 Color FD&C Yellow No. 6 0.004Orange flavor 0.020 Sodium benzoate 0.500

Purified Water to make 100 lit.

To a 150 liter vessel equipped with a stirrer is added 40 literspurified water and the 1-(o-chlorophenyl)-2- methyl-2-propylaminehydrochloride and the mixture is stirred until complete dissolution isachieved. The remaining ingredients are then added while stirring in thefol lowing order: sodium saccharin, sodium sucaryl, sodium benzoate,color and flavor. Stirring is continued until complete dissolution isachieved and. the volume is then adjusted to 100 liters with purifiedwater with subsequent stirring to insure uniformity.

EXAMPLE 7 An elixir, formulated to provide a dosage unit of about 0.050g. per dosage unit, is prepared as follows:

Ingredients: Kg.

l-(o-chloro phenyl)-2-methyl-2-propylamine hydrochloride 1.000 Sodiumsaccharin 0.020 Sodium sucaryl 0.200 Color FD&C Yellow No. 6 0.004Orange flavor 0.020 Sodium benzoate 0.500 Alcohol 10.000 Purified waterto make lit.

The procedure used to prepare the elixir is identical with that given inExample 6 for the preparation of the syrup except that the flavor isdissolved in the alcohol and this solution is the last ingredient added.

The pharmacologically active ingredient of the above compositions isprepared as follows (temperatures are given in degrees centigrade):

To a Grignard reagent (prepared from 50.0 g. of o,a-dichloro-toluene and7.45 g. of magnesium in diethyl ether) is added 18.0 g. of acetone atsuch rate that constant reflux is maintained. The reaction mixture isallowed to stand overnight at room temperature, and is then poured ontoa mixture of 20 percent sulfuric acid and ice. The organic layer isseparated, washed with water, an aqueous solution of sodium hydrogencarbonate and again with Water, dried over magnesium sulfate andevaporated to dryness. The residue is distilled under reduced pressureto yield 426 g. of 1-(o-chlor0-pheny1)- 2-methy1-2-propanol, B.P.120l22/ 12.5 mm.

To 29.0 ml. of glacial acetic acid, cooled to is added 11.5 g. of sodiumcyanide (98 percent) while stirring, and then dropwise 32.4 ml. ofconcentrated sulfuric acid, dissolved in 29 ml. of glacial acetic acid,while maintaining a temperature of Thel-(o-chlonophenyl)-2-methyl-2-propanol is added moderately fast,allowing the temperature to rise spontaneously. After completing theaddition, the reaction mixture is heated to 70 and stirred, and is thenpoured onto a mixture of water and ice. The aqueous mixture isneutralized with sodium carbonate and extracted with diethyl ether. Theorganic solution is washed with Water, dried over magnesium sulfate andevaporated to dryness.

The oily residue is taken up in 100 m1. of 6 N aqueous hydrochloric acidand refluxed until a clear solution is obtained. The latter is madebasic with aqueous ammonia and extracted with diethyl ether; the organicsolution is separated, washed, dried and evaporated. The residue isdistilled under reduced pressure to yield 26.3 g. of1-(o-chloro-phenyl)-2-methyl-2-propylamine, B.P. 116- 118/ 16 mm.

The l-(o-chl oro-phenyl)-2-methyl-2-propylamine hydrochloride isprepared by adding ethanolic hydrogen chloride to an icecold solution ofthe free base in ethanol; the desired salt precipitates and isrecrystallized from ethanol, M.P. 245246. Other salts, such as thesulfate, tartrate, citrate, methane sulfonate, naphthalene 2-sulfonateand the like, of l-(o-chloro-phenyl)-2-methyl-2- propylamine areprepared according to analogous procedures.

What is claimed is:

1. A method for the suppression of the appetite of a human, whichcomprises orally administering to said human a composition comprising apharmacologically effective amount of a member selected from the groupconsisting of 1-(o-chlorophenyl)-2-methyl-2-propylamine and apharmaceutically acceptable acid addition salt thereof, as the activeanoretic ingredient, and a pharmaceutically acceptable carrier.

2. A method of claim 1 for the suppression of the appetite of a human,which comprises orally administering to said human a compositioncomprising a pharmacologically effective amount of a pharmaceuticallyacceptable acid addition salt of l-(o-chloro-phenyl)-2-methyl-2-propylamine as the active anoretic ingredient, and apharmaceutically acceptable carrier.

3. A method of claim 1 for the suppression of the appetite of a human,which comprises orally administering to said human a compositioncomprising a pharmacologically effective amount ofl-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride as the activeanoretic ingredient, and a pharmaceutically acceptable carrier.

4. A method of claim 1 for the suppression of the appetite or a human,which comprises orally administering to said human a compositioncomprising from about 0.025 g. to about 0.075 g. of a member selectedfrom the group consisting of 1- (o-chlorophenyl -2-methyl-2-propylamineand a pharmaceutically acceptable acid addition salt thereof as theactive anoretic ingredient, and a pharmaceutically acceptable carrier.

5. A method of claim 1 for the suppression of the appetite of a human,which comprises orally adminstering to said human a compositioncomprising from about 0.025 g. to about 0.075 g. of a pharmaceuticallyacceptable acid addition salt of l-(o-chlorophenyl)-2-methyl-2-propylamine as the active anoretic ingredient, and a pharmaceuticallyacceptable carrier.

6. A method of claim 1 for the suppression of the appetite of a human,which comprises orally administering to said human a compositioncomprising from about 0.025 g. to about 0.075 g. of l-(o-chloro-phenyl)-2-methyl-2-propylamine hydrochloride as the active anoretic ingredient,and a pharmaceutically acceptable carrier.

7. A method of claim 1 for the suppression of the appetite of a human,which comprises orally administering to said human a compositioncomprising about 0.050 g. of l-(o-chloro-phenyl)-2-methyl-2-propylaminehydrochloride as the active anoretic ingredient, and a pharmaceuticallyacceptable carrier.

References Cited Ferrari: Chem. Abst., vol. 54, 1960, pp. 2024!: and209250.

ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

